Prognostic role of neuroendocrine differentiation in prostate cancer, putting together the pieces of the puzzle

Abstract

Neuroendocrine (NE) differentiation is a common feature in prostate cancer (PC). The clinical significance of this phenomenon is controversial; however preclinical and clinical data are in favor of an association with poor prognosis and early onset of a castrate resistant status. NE PC cells do not proliferate, but they can stimulate the proliferation of the exocrine component through the production of paracrine growth factors. The same paracrine signals may favor the outgrowth of castrate adapted tumors through androgen receptor dependent or independent mechanisms. Noteworthy, NE differentiation in PC is not a stable phenotype, being stimulated by several agents including androgen deprivation therapy, radiation therapy, and chemotherapy. The proportion of NE positive PC, therefore, is destined to increase during the natural history of the disease. This may complicate the assessment of the prognostic significance of this phenomenon. The majority of clinical studies have shown a significant correlation between NE differentiation and disease prognosis, confirming the preclinical rationale. In conclusion the NE phenotype is a prognostic parameter in PC. Whether this phenomenon is a pure prognostic factor or whether it can influence the prognosis by favoring the onset of a castrate resistance status is a matter of future research.

The proliferation marker Ki67, but not neuroendocrine expression, is an independent factor in the prediction of prognosis of primary prostate cancer patients

“…NSE staining seems to influence OS, but it was not confirmed as an independent prognostic factor in the multivariate analysis. These results are consistent with current published literature where strong evidence of NSE as potential prognostic factor is lacking (reviewed in 6 , 8 ), especially at early stages. 30 NED in PCa increases with higher histological grades 31 and disease progression, especially in response to androgen deprivation therapy.…”

“…Typical markers used to identify neuroendocrine differentiation (NED) in tumor tissue are neuron specific enolase (NSE), chromogranin A (CgA) and synaptophysin (Syp). 1 - 3 Neuroendocrine differentiation, measured by one or more of those markers, has been associated with disease progression 4 or poor survival in prostate cancer 5 , but up to now its prognostic value has not been clarified because of controversial results 6 ; 7 , 8 . However, Epstein et al 9 have recently suggested using neuroendocrine markers to better characterize and classify NED in prostate cancer.…”

Neuroendocrine Transdifferentiation in Human Prostate Cancer Cells: An Integrated Approach

“…These peptide hormones and biogenic amines can either be released into the bloodstream or act locally by paracrine or autocrine signaling in an androgen-independent way (7). Neuroendocrine cells and the associated neuropeptides play also a crucial role in sustaining both growth and progression of many, if not all, conventional prostate adenocarcinomas (8,9) with a wide preclinical and clinical evidence of a poor prognosis correlation (10). However, the nature and the origin of neuroendocrine cells in prostate tumor lesions and their underlying molecular mechanisms are still controversial.…”

Prognostic and Predictive Biomarkers for Castration Resistant Prostate Cancer

“…Neuroendocrine differentiation is a common feature of prostatic adenocarcinomas and is usually determined by immunoreactivity for neuroendocrine markers (e.g., chromogranin A, neuron specific enolase) (Vashchenko and Abrahamsson 2005). Neuroendocrine differentiation is associated with castrate-resistant status and worse prognosis in CRPC (Berruti et al 2010). In Komiya's study, neuroendocrine differentiation was evaluated in men with hormone-sensitive and castration-resistant prostate cancer, by using IHC staining in the biopsied prostate tissue.…”